Chemotherapeutic drugs induce the activation of proteins associated with tumorigenesis and drug resistance in low aggressive tumor cells.

BIGI, MARÍA MERCEDES; MARTÍNEZ PONCE, PALOMA ; RIOS MEDRANO, MAYRA AGUSTINA; ORLANDO, ULISES DANIEL

Mendoza

Congreso; Congreso SAIB 2022 Reunión anual Edición LVIII; 2022

Sociedad Argentina de Investigación Bioquímica y Biología Molecular

Acyl CoA synthetase 4 (ACSL4) is an enzyme which regulates steroidogenesis in normal physiological conditions. However, in pathological scenarios, an increase in ACSL4 expression is associated with the promotion of a highly aggressive cell phenotype in breast, prostate, colon and liver cancer. ATP-binding cassette (ABC) transporters are transmembrane proteins which use energy through ATP hydrolysis to translocate low-weight molecules. In normal physiological conditions, these transporters are in charge of maintaining homeostasis in different tissues. In contrast, their participation in pathological events is associated with drug resistance through chemotherapeutic drug efflux, among other events. Chemotherapeutic drugs inhibit the uncontrolled growth and proliferation of cancer cells, while cell resistance to drugs, either existing before treatment or generated after therapy, is responsible for most relapses in cancer, one of the major causes of death from the disease. We have shown that ACSL4 takes part in the resistance to chemotherapeutic agents by regulating the expression of ABC transporters; thus, the objective of this work was to study the effect of chemotherapeutic drugs on ACSL4, ABCG2 and ABCC4. The experimental model consisted in challenging H295R adrenal and MCF-7 breast cancer cell lines, characterized by low aggressive phenotypes and low expression of ACSL4, ABCG2 and ABCC4 proteins, with non-lethal doses of doxorubicin (20 nM) and cisplatin (200 nM). We evaluated cell functionality using viability (MTT) and proliferation (BrdU) assays, and compound exclusion (efflux) using fluorescent doxorubicin and Hoechst 33342. ACSL4, ABCG2 and ABCC4 were evaluated by western blot (WB). Treatment with doxorubicin and cisplatin improved H295R and MCF-7 cell viability (MTT-p